Compounds useful as anti-inflammatory agents which are -alkyl-4-acyl-6-tert-butylphenol compounds, especially 4-acyl-2,6-di-tert-butylphenol compounds, and related derivative thereof, where the 4-acyl substituent has a terminally unsaturated moiety, are disclosed in U.S. Pat. No. 4,708,966 issued to Loomans, Matthews & Miller on Nov. 24, 1987; U.S. Pat. No. 4,847,303 issued to Loomans, Matthews & Miller on Jul. 11, 1989; and U.S. Pat. No. 4,949,428 issued to Dobson, Loomans, Matthews & Miller on Jul. 18, 1989. A process for making such compounds is disclosed in U.S. Pat. No. 4,982,006 issued to Hudec on Jan. 1, 1991.
Friedel-Crafts reactions of aromatic hydrocarbons with acyl halides in the presence of a catalyst such as anhydrous aluminum chloride to produce aromatic compounds having an acyl substituent are well-known. But when the acyl moiety has a labile portion, such as the terminal unsaturation of the compounds of interest herein, side reactions often occur resulting in poor yield and purity of the desired product.
The use of trifluoroacetic anhydride to aid the reaction of an aromatic compound and a carboxylic acid is known; see, e.g., Tedder, J.M., "The Use of Trifluoroacetic Anhydride and Related Compounds in Organic Syntheses", Chemical Reviews. Vol. 55 (1955), pp. 787-827; Galli, C., "Acylation of Arenes and Heteroarenes with in situ Generated Acyl Trifluoroacetates", Synthesis. April, 1979, pp. 303-304; Nishinaga, A., T. Shimizu, Y. Toyoda & T. Matsuura, "Oxygenation of 2,6-Di-tert-butylphenols Bearing an Electron-Withdrawing Group in the 4-Position", Journal of Organic Chemistry, Vol. 47 (1982), pp. 2278-2285. However, when the carboxylic acid reactant has a labile portion, such as a terminally unsaturated moiety, unwanted side reactions can occur, see, e.g., Tedder at page 800. Thus, the ability of such a reaction scheme to prepare 2-alkyl-4-acyl-tert-butylphenol compounds where the 4-acyl substituent has a terminally unsaturated moiety was unknown and unpredictable prior to the invention disclosed herein.
It is an object of the subject invention to provide a process for the preparation of certain 2-alkyl-4-acyl-6-tert-butylphenol compounds, where the acyl substituent has a certain terminally-unsaturated moiety.
It is a further object of the present invention to provide a process for the preparation of such compounds from the corresponding 2-alkyl-6-tert-butylphenol and carboxylic acid reactants with good yield.
It is a still further object of the present invention to provide a process for the preparation of such compounds which provides the compounds at high purity and high yield.